The present invention relates to a series of novel quinoline-carboxylic acid derivatives which have been found to have valuable and powerful antibacterial activity. The invention also provides compositions containing these compounds, methods of using them and processes for preparing them.
The compounds of the present invention are 1-substituted-4-oxo-6-(fluoro or chloro)-7-(optionally substituted heterocyclic)-8-alkoxy-quinoline-3-carboxylic acid derivatives.
It is an unfortunate fact of modern medicine that many infectious bacteria are gradually developing resistance to the antibiotics commonly used to treat infection caused by them, with the result that known antibacterial agents are increasingly becoming of limited effectiveness. There is, therefore, a continuing need to develop new antibacterial agents, which may, even if only for a restricted period, be effective against infectious bacteria. Most of the common antibacterial agents in present day use were originally developed from fermentation products, although some are of wholly synthetic origin.
There have been proposals to use certain 4-oxoquinoline-3-carboxylic acid derivatives as antibacterial agents. For example, European Patent Publication No. 78 362 discloses a limited class of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carb oxylic acid derivatives, in which the piperazinyl group is unsubstituted or has a methyl, ethyl or .beta.-hydroxyethyl substituent at the 4-position. These compounds resemble certain of those of the present invention, except that they lack the 8-alkoxy group which has been found to be critical to the compounds of the present invention.
European Patent Publications No. 106 489 and No. 153 163 disclose classes of quinoline derivatives, including amongst many others, a few 1-substituted-4-oxo-1,4-dihydro-6-halo-7-(optionally substituted heterocyclic)-8-substituted-quinoline-3-carboxylic acid derivatives, of which in some the 8-substituent is an alkoxy group, and which, in this respect, resemble the compounds of the present invention. However, these prior art compounds differ from those of the present invention in the nature of the 7-substituent.
Of the compounds disclosed in European Patent Publication No. 78 362, one, namely Norfloxacin, whose systematic name is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxyli c acid, is disclosed in The Merck Index Tenth Edition, published in 1983, monograph number 6541. In common with the other compounds of European Patent Publication No. 78 362, this lacks the critical 8-alkoxy substituent of the present invention.
We have surprisingly found that the combination of a limited class of 8-alkoxy substituents with certain limited and highly specific classes of heterocyclic substituent at the 7-position leads to the production of compounds which have unexpectedly good antibacterial activities, in many cases far surpassing those of the prior art compounds. In particular, the compounds of the present invention have surprisingly good activity against several strains of bacteria against which the known compounds are ineffective or are effective only at high concentrations, for example Staphylococcus aureus 535, Enterococcus faecalis 681 and Escherichia coli 609.